Additional Links:

Quotes by Mike:

“In all of my submissions... I try to tell a story... I want to make a readable document.”

“The data is the data, but we can present that data in many different ways.”

“I want to demonstrate at the end of the day that I know what I’m doing.”

Transcription:

Announcer: Welcome to the Global Medical Device podcast where today's brightest minds in the medical device industry go to get their most useful and actionable insider knowledge, direct from some of the world's leading medical device experts and companies.

Jon Speer: How many of you think that you have a firm grasp and understanding of what substantial equivalence means as it relates to regulatory submissions especially to a 510(k)? Well, I got news for you. There is a large percentage of 510(k)'s that are rejected because of poor substantial equivalence. So clearly there's something that we in the industry can learn about this particular topic. And that's why Mike Drues and I chat about substantial equivalence on this episode of The Global Medical Device podcast.

Jon Speer: Hello and welcome to the Global Medical Device podcast. This is your Host, the Founder and VP of Quality and Regulatory, at greenlight.guru, Jon Speer, and with me today, I have my good friend, Mike Drues from Vascular Sciences. Hello Mike.

Mike Drues: Hi Jon.

Jon Speer: Well, today, I thought we would talk about something that I know you are very involved with and it's something that I'm sure you deal with probably on a daily basis, and it's that fun topic of demonstrating substantial equivalence, and really what does all that even mean? I know that's something that confuses people quite a bit.

Mike Drues: Well, you're exactly right, Jon. And as we'll discuss today, the concept of substantial equivalence has been around now for 41 years since 1976 when the 510(k) was created, and still, 41 years later, I still don't think we're very much closer to answering the question: What exactly does substantial equivalence mean? [chuckle]

Jon Speer: Well, maybe that's probably a good place to start. I know that's a term that's thrown around. People, they're trying to understand, well, what does substantial equivalence mean, why does that apply to me, why is that important? So maybe if you could take a moment or two and let everyone know a little bit of why substantial equivalence, why would you care about this topic?

Mike Drues: So that is a great place to start, Jon. So substantial equivalence is important for a couple of reasons. First of all, to remind you and your audience of some statistics, 75% of 510(k)'s that are submitted to the FDA today are rejected, first time out of the box. And of those that are rejected, 85% of them are rejected specifically because of substantial equivalence or the lack thereof. Yes, I know that a lot of 510(k)'s are rejected on administrative review because of the Refuse to Accept guidance for example, but we're not talking about administrative review, we're talking about the substantive or the scientific review. So 85% of 510(k)'s that are rejected on scientific review are rejected because of substantial equivalence. That's reason number one, why substantial equivalence is important. Reason number two that substantial equivalence is important is because it's one of the two key parts, the two key components of the 510(k). In order to have a successful 510K you need to have a very strong substantial equivalence argument, and you have to have a rock solid risk mitigation strategy. So substantial equivalence is one half of that 510(k) equation.

Jon Speer: Alright, well that certainly starts to shed a little bit of light on this, why I as med device developer need to worry about substantial equivalence. But okay, it's clear that it's a big deal when it comes to 510(k)'s and it's clear that we as an industry probably aren't faring so well on the substantial equivalence front. So maybe take a moment or two and let's talk a little bit about what is substantial equivalence and maybe we could get into a little bit of how I would demonstrate that and all those sorts of things. So let's start, what is it? What does that even mean?

Mike Drues: I'm happy to do that, Jon. And again, just leading into that, just reflecting back to those statistics for a moment. So many people think that substantial equivalence is such a no-brainer, pardon the pun, but if it is, then how do we explain those statistics that I just shared? So substantial equivalence is not nearly as simple as a lot of people think. So fundamentally, when we talk about the substantial equivalence, the challenge that we're talking about here, the question that we're asking is, how different can two medical devices be both in terms of labeling as well as technology and yet still be similar enough, close enough to be substantial equivalent. Now of course FDA has put out a number of guidances over the last 41 years to try to address that question to try to inquiry to that question, but as I said earlier, and I really mean this, there is no answer, certainly no simple answer to that question. It's up to us. We have to go into the FDA, and we have to argue that our device is basically the same, or substantially equivalent addressing as we talk about the two components of substantial equivalence, labeling and technology. And in my approach, substantial equivalence when I address that, I address labeling separately and technology separately.

Mike Drues: Most people do not do that, but that's another reason why most submissions are rejected. So for example, on the labeling side, I will create a labeling matrix as I like to call it, where I show the labeling for our device, and I show the labeling... I'm talking about high-level labeling here indication of use or intended use for our predicate device or our predicate devices. If there's more than one. And I will literally do a word to word comparison, and I'd actually take it a step further. I like to highlight these in different colors. So for example, the words that are the same in my device versus the predicate, I will highlight those in green. The words that are similar but are not exactly the same, I will highlight those in yellow. And finally, the words that are very different, I will highlight those in red. So simply put, what I'm doing graphically, is I'm stressing the similarities. In other words, the more green that I have in that labeling table, the more likely I will be successful with a 510(k), alternately, the more red that I have in that table, the more likely I might want to consider the de novo for example.

Mike Drues: So for the words that are the same in green, I say, "These are the same words. End of discussion. Let's move on to the next point." For the words that are in yellow, I say, "These are very similar, but the differences don't matter. And here's why", and finally for those words that are in red, that's where we have to do a little heavy lifting, that's where we have to show that, yes, these are significant differences, but still the device is substantially equivalent anyway. For example because it does not introduce any new questions about safety, or risks, or anything like that? And then I do exactly the same on the technology side, I will create what I call a technology matrix where I compare the technology, of my device with the technology of the predicate, and I would do the same thing with the highlighting in different colors. Emphasizing the similarities and explaining the differences. Does that make sense, Jon?

Jon Speer: I think so. So let me ask maybe a clarifying question or maybe a point to make sure that it's clear. So in this matrix that you're constructing the items that you highlight yellow, that identifies the similar items and so then you provide some narrative to explain the dis-similarities and the same would be true for the things that you highlight in red, where they're different, you again provide some narrative to give some explanation of why it does not matter as... Do I have the concepts?

Mike Drues: Yes, that's correct. In many cases, I would say actually and virtually in all cases, I do provide narrative and depending on exactly what the, what the situation is especially on the technology side, I might not just provide a narrative, a written explanation, but I also might include data. I might include testing as to, "Here's the technological parameter of my device in this particular range, and the predicate is the same range", or something like that. I see a lot of submissions as many in your audience may remember Jon. I also work as a consultant for the FDA, so I see this from both sides, I see a lot of submissions come in, where there is only data, only numbers with no explanation with no narrative whatsoever. And that is, in my opinion, not a very good approach. What I try to do with all of my submissions and even my pre-subs and all of my documentation, to be honest, is I try to tell a story. I try to write this kinda like a novel. Where there's an introduction, there's a series of main points, there's a conclusion. I wanna make a readable document.

Jon Speer: Sure. That makes a lot of sense. I mean... And that's really what we're doing with any sort of regulatory submission is we're not just throwing data over the wall, we're telling a story and we should, that I guess established the plot in the way that we want the reader to interpret and understand things, hopefully in our favor. And so the story is, it's certainly important.

Mike Drues: That's a great metaphor, Jon and I use a similar metaphor from politics, frequently, and that is to spin.

Jon Speer: Yeah.

Mike Drues: Is the glass half empty or half full. Those both are factually correct statements, but data is the data, but we can present that data in obviously many different ways.

Jon Speer: So let's talk a little bit about that story of our substantial equivalence and you already shared some of the statistics from how often unfortunately we as an industry get substantial equivalence wrong in the eyes of the FDA. But what happens if you get it wrong?

Mike Drues: Well, first of all, we have to be a little bit careful. Sometimes we do in fact, get it wrong, but more often than not, it's not a matter of right or wrong, it's more we haven't convinced the FDA to buy into our argument...

Jon Speer: Yeah, got it.

Mike Drues: To buy into our position. So it's not... Once again, Is the glass half empty or half full? It's not a matter of right or wrong. True or false. Black or white. It's a matter of convincing. When I go into the FDA with a 510(k), or any other kind of submission for that matter, I view this very much like a sales and marketing objective. In other words, I'm trying to sell the FDA, not in a monetary sense, but I'm trying to sell the FDA on my regulatory logic; in this particular case, on my substantial equivalence rationale.

Jon Speer: Sure.

Mike Drues: So, what happens when companies do get it wrong, or at the very least, are not successful in selling the FDA with their substantial equivalence, well simply put, usually nothing good happens. Usually you're talking about more time, more money, sometimes you're even pushed into a more rigorous regulatory pathway; like for example, a PMA. And I'll give you a quick example. There was an In Vitro diagnostic company that made a submission to the FDA not long ago. They were unsuccessful with their 510(k) specifically in showing substantial equivalence. But it took the FDA 10 months to come back and tell the company that this device is not substantially equivalent; NSE. And so just imagine the amount of, not just time but money, that was wasted in this whole back and forth process. And you and I have talked about before Jon, I think this is a very amateur mistake. I don't think there's any situation where a 510(k) should be rejected because of substantial equivalence. I think we can greatly mitigate the chances of that happening, possibly even eliminate the chances of that happening, taking the technology to the FDA long in advance of the submission in the form of a pre-submission meeting or something else.

Jon Speer: Sure.

Mike Drues: So again, I see a lot of companies doing this but I think it's a very amateur mistake.

Jon Speer: Sure. Alright. So let's get into maybe a little bit more of the meat of this. I'm a med device company. I'm preparing a submission and I need to demonstrate... I'm putting together a 510(k). I need to demonstrate substantial equivalence. So, how do we show that? How do we demonstrate a substantial equivalence?

Mike Drues: So my approach, which is admittedly different than the approach that many other take, but I don't wanna be in that 75% that are rejected. I wanna be in the 25% that are not and fortunately, I am. The way I achieve that, as I alluded to earlier, is I de-couple the two components of substantial equivalence. That is, labeling and technology, and I address them separately by creating the labeling matrix and creating the technology matrix. But I don't stop there. I go well beyond what the regulation requires. I also look at the product code. So for example, if my product code, sorry, if my predicate's product code is X, Y, Z, my product code is probably going to be the same X, Y, Z, although not always, but more often than not it is. I will also provide a rationale, a justification, as to why my technology is appropriate for that particular product code and not for another product code. And by the way, let me go back to predicates for just a moment. I will usually not just talk about the predicate that I'm using, but I will also talk about other possible devices that might be considered predicates and why I am not using those. In other words, I want to do all that I can to remove all the possible reasons why FDA might come back and say, "This is not substantially equivalent."

Jon Speer: Sure.

Mike Drues: I wanna be very proactive. I wanna be very prophylactic in what I'm doing. I wanna demonstrate, at the end of the day, that I know what the heck I'm doing. I've considered the labeling. I've considered the technology. I've considered the product code. I will also moot an argument in there as to the classification justification. If your predicate is Class II, for example, and you're successful with your substantial equivalence argument, then your new device will also be Class II. But I don't make that assumption. I will also put a justification, usually not that long, but at least a few paragraphs, as to why Class II is the appropriate classification for my device. Again, I wanna remove all the possible reasons why FDA could come back and say, "This device is not substantially equivalent. So, bottom line when it comes to substantial equivalence Jon, for me, it's fairly simple. I want to stress the similarities and at the same time I want to de-emphasize, or at the very least, not draw attention to the differences. And any differences that are present, I need to be able to mitigate them or maybe even completely dismiss them, so that they're not relevant to our discussion. So maybe we should take a look at some examples Jon?

Jon Speer: Well, I do wanna talk about some examples. But there was a couple of things that, one, I wanna clarify to the audience 'cause I've heard some confusion from time to time on the topic of product code. So let's talk... Let me share a little bit about product codes. So, FDA has identified, I don't even know the count, but hundreds, thousands of different product codes, and these product codes are three letter codes that relate to the type of device that you have and the product code then all sit under different regulations that also relate to the specific type of device or category of products that you're developing. And like, for example, one regulation may have... It could considerably have dozens of different product codes that relate to that. And every device that gets cleared through a 510(k) is assigned a primary product code. You as the submitter usually will define that, initially sometimes that changes from an FDA perspective and sometimes not quite as common but sometimes there might be secondary product codes that might be assigned. So, whenever you're looking at predicate devices, you will be able to see on their 510(k) summary, what product code was designated to that.

Jon Speer: So that's an important thing to identify. That's what Mike was mentioning. And then Mike I wanna highlight something that that you talked about, you talked about identifying the predicates that you're using, but you also talked about other devices that might have similar product codes, or regulations in that same kind of category as the product that your demonstrating or that you're submitting that you chose not to use as predicates with an explanation. I wanna just to maybe dive onto that of just a little bit because that's a little bit of a novel approach. Can you talk maybe a little bit more about that and add a few more words about that?

Mike Drues: Sure. I'd been happy to Jon. The regulation says, in order to have a 510(k), we have to have a predicate. The regulation does not say how close or alternatively, how distant that, how different that predicate can be. The regulation also does not say how recent or how old that predicate can be. And in my opinion, the regulation should not say anything about how close it is, in terms of technology or how recent it is in terms of time. That should be totally up to us. So, everything else being equal, I will choose a predicate that is as similar, as possible to my technology, I will choose a predicate that is as recent as possible, in terms of time. But there are many cases where I don't do that. For example, if it's to my advantage, to choose a predicate that is more distant in terms of technology or is older... Let's say, for the sake of discussion that I have a couple of different predicates that I can use. One that was brought to the market a year ago, and the other that was brought to the market a decade ago, and let's say for whatever reason the product that was brought on to the market a decade ago, was more, is more appropriate to make my substantial equivalence comparison than the one from last year.

Mike Drues: So I will say to the FDA. And by the way, I do this in my pre-sub first and then I do it also in my submission. I say to the FDA I'm gonna compare my device to this device that was brought on to the market a decade ago. And before I explain why you probably remember that there was another device, a similar device that was brought out to the market last year. Let me first explain to you why I am not using that device. So once again Jon, I'm trying to remove as many possible reasons why FDA can disagree with me as I possibly can in advance before they even...

Jon Speer: Right, right.

Mike Drues: So simply put the regulation says there has to be a predicate, it doesn't say how similar it needs to be, nor does it say how recent, or how old that it needs to be. Some people, by the way, have suggested that we add regulation along those lines? I'm adamantly against that for a variety of reasons. But that should be up to us as professionals. That's kind of like micromanaging a surgeon. A good surgeon will know how to do the procedure to get the best outcome for the patient. A good regulatory consultant will know how to get the best outcome for that particular medical device. And I don't want regulation to get in my way too much of that.

Jon Speer: Alright, I appreciate you going into a little bit more depth on that. So yes, you suggest that we talk about some examples, lets talk about a few examples?

Mike Drues: Sure, so I'm a big fan of Albert Einstein. Einstein was a very, very smart guy, much smarter than me. And Einstein said, "If you can't explain something simply you don't understand it well enough." So I try to use very simple metaphors that everybody can relate to rather than using medical devices that would probably require some knowledge of engineering, or medicine. Lets use some examples that everybody can relate to.

Jon Speer: Okay.

Mike Drues: So starting out by comparing an apple to an orange. If we were going to walk into the FDA wanting to argue that an apple is substantially equivalent to an orange... Let me put you a little bit on the spot Jon, how would you do that?

Jon Speer: Sure. So I would talk a little bit about the nutritional value of each of the apple and the orange and how they're similar and substantially equivalent. I would talk about how they're both fruits that grow on trees. I would talk about the vitamins and the minerals and all the substances that might be contained within each of those that are the same.

Mike Drues: So, you're exactly right Jon. And for the benefit of the audience, let me point out what Jon is doing, he's doing step one of my substantial equivalence logic and that is stressing the similarities. So, both the apple and the orange are fruits, they both grow on trees, they both have skins, they both have seeds they both provide nutrients and calories, and so on, and so on. So step one is to stress the similarities. Would you stop at that point, Jon?

Jon Speer: Would I stop at that point? So it's not much labeling for an apple and an orange but I suppose if we're gonna buy apples in the store and the oranges in the store they're gonna be potentially in some sort of container or bag that may have some sort of label and I might identify some of the similarities on their packaging, that might be pertinent to the discussion. I don't know. Should I dive deeper? It felt like that might be a leading question.

Mike Drues: It was. I was hoping that it was a leading question. You did brilliantly on step one, stressing the similarities.

Mike Drues: What I was hoping to lead you to is, step two, which is de-emphasizing or not drawing attention to the differences.

Jon Speer: Oh, I see. Yeah. Yeah.

Mike Drues: And so, let's again, use the apple and the orange as an example. So, they're both fruits, but they are different fruits. They both have skins, but in the case of the apple, most people eat the skin. In the case of the orange most people do not. They both provide nutrients, but maybe the nutrient content for an apple is a little bit different than an orange. So, for each of those differences, we have to, first of all, acknowledge the difference, but then we have to mitigate it. We have to say, "Yes. There is a difference in nutritional value but both fall within the recommended daily allowances for vitamin C or what have you, and therefore it's not important."

Jon Speer: Right.

Mike Drues: So, step two of the substantial equivalence logic is de-emphasizing or not drawing attention to the differences. And then any differences that are there, we have to mitigate them. Now taking this even a step further Jon, sometimes I will bring up a difference prophylactically, that is, without FDA even asking me about it. But other times I might not bring up that difference prophylactically because maybe I don't want to address it unless I have to.

Jon Speer: Right.

Mike Drues: And I will wait to see if FDA brings it up. If FDA doesn't ever bring it up, then I don't have to address it. If FDA does bring it up, then I will be prepared in advance to address that difference

Jon Speer: Okay.

Mike Drues: So this is all part of the poker game, as I've described this before, knowing not just which cards to play, but when to play them and how. So again, step one is stressing the similarities. Step two is de-emphasizing or not drawing attention to the differences. Let's use one more metaphor.

Jon Speer: Okay.

Mike Drues: And how about comparing a car to a truck?

Jon Speer: Sure.

Mike Drues: If we were wanting to bring a car to the market by comparing it to a truck, how would we do that Jon? What would be the regulatory logic?

Jon Speer: Well, there's all kinds of similarities between cars and trucks Mike. They have four wheels. They have engines. They have steering wheels. They have seats on the interior. They have a frame and a chassis. And of course we can go on and on and on and list all the specific details of a car and a truck that are the same. They transport people. They go a certain velocity and contain fuel to make them go and all those sorts of things.

Mike Drues: Well, once again Jon, you've done a brilliant job on step one, of stressing the similarities. Both are vehicles for transportation. Both travel on roads. Both have engines. Both consume fuel and on and on and on. Step two, of course, is to de-emphasize or not drawing attention to the differences.

Jon Speer: Sure.

Mike Drues: So both are vehicles. But usually trucks are much larger than cars. Both have engines, but usually cars might burn gasoline or perhaps electricity, if it's a hybrid. Trucks usually burn diesel.

Jon Speer: Right.

Mike Drues: Both are vehicles are for transportations, but cars are usually designed to carry people and a small amount of cargo. Trucks, on the other hand, like an 18-wheeler for example, are designed to carry very large amounts of cargo. So, just like in the apples and the oranges, we have to stress the similarities and de-emphasis and mitigate the risk of the differences. Now, let's use that metaphor to go even one step further. It depends on what kind of truck. So, if you had a choice between comparing your car to an 18-wheeler, versus a car to a pick-up truck, everything else being equal Jon, which would you choose?

Jon Speer: Well, I'm gonna choose the pick-up truck because it is gonna be the most similar to my car as far as its form and function.

Mike Drues: You're exactly right. A pick-up truck, everything else being equal, is going to be a closer comparison to a car than to an 18-wheeler. But remember, as we talked about before Jon, the regulation does not say how close or how far your predicate needs to be. So if it is to my advantage to compare my car to a 18-wheeler, I will do that. But before I do, I will say, "You might be wondering why I'm not comparing it to a pick-up truck. Well, here's why. And then let me tell you now why the 18-wheeler is the appropriate comparison."

Jon Speer: Okay.

Mike Drues: Simply put, sometimes people they misunderstand why I'm using these very simple metaphors. Well, it goes back to Einstein. If you can't explain something simply you don't understand it well enough. Everybody knows what apples and oranges are. Everybody knows what cars and trucks are. If we cannot explain the regulatory logic, based on these simple products, How can we possibly use this regulatory logic, which is the crux of the 510(k), on much more complicated technologies that you and I and the rest of the audience are involved with? And the last example that I just wanted to point to is actually an example demonstrated in a video that's been floating around on the internet for many years Jon, that you did yourself. And that is your infamous ketchup versus mustard video.

Mike Drues: And, I'll be honest with you Jon, I think that's an absolute brilliant video. And as you know, I use that in many of my medical device trainings. So, I encourage all of your audience if you have not seen Jon's video, where he does a similar substantial equivalence comparison that I just did with apples and oranges and the cars and trucks. He does it with ketchup and mustard. I would highly recommend watching that video.

Jon Speer: Alright, Mike, that's a blast from the past. I haven't seen that video, myself in a while, but I was quite the young pup or younger anyway. [chuckle] But now...

Mike Drues: Well, I wasn't gonna mention that part Jon.

Jon Speer: Yeah, I was gonna say I have less hair than I do now, but I was still bald but lets just say that the facial hair is a lot more gray than it was then. But folks, I'll... I'll provide a link to that video with the text that accompanies that this podcast, but that's a blast from the past. Thanks for reminding me of that. I had for a moment forgotten about that one Mike. Alright so...

Mike Drues: I use that video frequently in many of my medical device trainings.

Jon Speer: Thank you I appreciate that. So let's... I guess jump into some final thoughts and key takeaways and it may be a lesson or two that can be learned. What do you think? How can we help this... How can we help our peers in this industry, remove the substantial equivalence block that prevents so many 510(k)'s from getting through.

Mike Drues: So simply put, we've gone through a lot in a short period of time, but if we were to recap, remember a couple of things. Remember, substantial equivalence is important and why it's important because so many of the submissions are rejected because of that. In order to show substantial equivalence you have to address both labeling as well as technology. You do not have to decouple them. As a matter of fact most people do not. However, I personally do decouple them. I treat them separately. I show substantial equivalence for labeling and substantial equivalence for technology separately. You don't have to do that but that's my approach. You can do that via the labeling matrix and the technology matrix as we talked about. But fundamentally remember the apples and oranges and cars and trucks, we wanna stress the similarities and we want to de-emphasize or not draw attention to the differences. And last and most important perhaps, is once you have developed your, identified your predicate look at the product code, justified the classification and everything else, please take this to the FDA in advance in the form of a pre-sub or whatever way that you want to choose to communicate with the FDA.

Mike Drues: Quite frankly, I don't really care, but if the first time that the FDA is seeing your regulatory strategy, including your substantial equivalence argument. If the first time that they're seeing it is in your actual 510(k) submission, that in my opinion is a huge mistake because you're taking a huge regulatory risk that that submission is going to get kicked back. Not necessarily because you were wrong, but because you were not successful in convincing the FDA. This is very much like a prosecution in a defense. If the prosecution is unsuccessful in convincing the jury does that mean that they're wrong, does that mean that the person is not guilty? No, that's not what it means. It means that they were unsuccessful in convincing the judge or the jury of their position. So take this to the FDA in advance, make sure that everybody is on the same page that everybody is pulling in the same direction, and that will greatly minimize perhaps not completely eliminate but greatly minimize the chances of problems further down the road. Those are just a few of the pieces of advice that I would give your audience. There's obviously much much more that we can talk about on this topic and I look forward to doing that at some time in the future.

Jon Speer: Alright, well, Mike, I appreciate the insights on substantial equivalence. Folks, a big part of any sort of regulatory submission and product development effort is certainly rooted in good design control practices and risk management and the number one software in the world to help you with those types of activities is developed and produced right here at greenlight.guru. So be sure to go to www.greenlight.guru and learn more about not only our design control and risk management workflow but all the other workflows that we've developed to help companies with their quality management system. Again, I wanna thank Mike Drues from Vascular Sciences for being my guest today, and this is your host, the founder of VP of Quality and Regulatory at greenlight.guru, Jon Speer and you have been listening to the Global Medical Device podcast.

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